Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.

Autor: Sloman DL; Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Noucti N; Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Altman MD; Chemistry Modeling and Informatics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Chen D; Drug Metabolism and Pharmacokinetics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Mislak AC; Drug Metabolism and Pharmacokinetics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Szewczak A; CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Hayashi M; CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Warren L; CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Dellovade T; Core Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Wu Z; Core Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Marcus J; Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Walker D; Pharmaceutical Research and Development, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Su HP; Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States., Edavettal SC; Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States., Munshi S; Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States., Hutton M; Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Nuthall H; Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States., Stanton MG; Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Sep 01; Vol. 26 (17), pp. 4362-6. Date of Electronic Publication: 2016 Feb 06.
DOI: 10.1016/j.bmcl.2016.02.003
Abstrakt: Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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